Maple syrup disease – causes, symptoms & therapy

Maple syrup disease is based on a genetic defect that prevents the breakdown of branched-chain amino acids . These accumulate in the blood and cause symptoms of poisoning in the body. An intermediate product of the disturbed amino acid breakdown is the carboxylic acid ester sotolon, which occurs, among other things, as a flavoring in maple syrup . Along with the branched-chain amino acids, sotolone is also excreted in the urine, causing the characteristic maple syrup odor. This aromatic smell has given the disease its name. Maple syrup urine disease is also known as branched chain disease. It is a very rare hereditary disease, which, however, occurs increasingly in Georgia and among the Mennonites in Pennsylvania. If left untreated, the disease quickly leads to death. With strict dietary management, the prognosis is good.

causes

  There is no single cause for maple syrup disease. What all sufferers have in common, however, is that they suffer from a genetic disorder. However, maple syrup disease is a disease complex that is based on different mutations . The branched-chain amino acids are broken down by an entire enzyme complex that is divided into several subunits. The first two subunits of the so-called alpha-keto acid dehydrogenase complex are represented by enzymes encoded by the genes BCKDHA on chromosome 19, BCKDHB on chromosome 6 and DBT on chromosome 1.These enzymes are responsible for breaking down the amino acids valine, leucine and isoleucine. If one of these genes is mutated, these amino acids will not be degraded, or not sufficiently so. The third subunit of the alpha-keto acid dehydrogenase complex is responsible for the breakdown of these amino acids in the liver , leukocytes and fibroblasts. The corresponding enzyme is encoded by a gene on chromosome 7. This is a particularly severe form of maple syrup disease. A milder form of the disease is caused by a mutation in the regulatory gene PPM1K on chromosome 4.

In addition, in the intermediary metabolism of leucine, a carboxylic acid ester called sotolon is produced in all forms of the disease. This also accumulates in the blood and is excreted in the urine. Sotolone is also found in maple syrup, where it creates the characteristic smell that characterizes this syrup. However, this is why the patient’s urine, enriched with Sotolon, smells of maple syrup. Maple syrup disease is characterized by the accumulation of the branched-chain amino acids valine, leucine and isoleucine and their breakdown products (keto acids and others) in the blood. This leads to metabolic acidosis , hypoglycemia , impaired uric acid synthesis and inhibited myelination of nerve cells.

When to the doctor?

If there is a suspicion of maple syrup disease, a doctor must be consulted in any case. If those affected suffer from vomiting, coordination disorders, refusal to eat or seizures, they should see a doctor immediately. Newborns in particular must be presented to a doctor if they refuse to eat. The same applies if the newborn develops a drinking disorder, apathy, seizures or even a comatose state. The baby also needs to see a doctor if their head is tilted backwards.

If the extremities and trunk are overstretched, the baby needs immediate medical attention. If the smell of the urine is reminiscent of maple syrup or maggi, a doctor’s visit must take place in any case. If the disease remains undetected or untreated, it can lead to death within a very short time.

If those affected always suffer from recurrent vomiting and from motor and mental retardation, they must consult a doctor. In the case of failure to thrive and impaired coordination of movements, those affected should not hesitate to consult a doctor. In the case of lethargy, coma, ataxia or opisthotonus, an emergency doctor must be contacted immediately.

symptoms and course

Typical symptoms of maple syrup disease:

• Vomit

• coordination disorders

• refusal of food

• seizures

There are several forms of maple syrup disease. These include the classic, intermediate, intermittent and thiamine-dependent form. The symptoms of classic maple syrup disease already appear in the first week of life of the newborn. Refusal to eat, poor drinking, apathy , seizures and even comatose states appear. The head is bent backwards. The extremities and trunk are hyperextended. The smell of maple syrup or Maggi in the urine is also typical.

If left untreated, the disease leads to death within a short period of time through the development of severe ketoacidosis. The intermediate form of maple syrup disease is usually milder. Ketoacidosis is rare. However, those affected suffer from recurring vomiting, motor and mental retardation, failure to thrive and impaired coordination of movements. In the intermittent form of the disease, symptoms appear only as part of catabolic processes in the body.

During the catabolic processes, the body’s own protein is increasingly broken down as a result of infections and other disease-related processes. The branched-chain amino acids released in the process then accumulate in the blood. At normal concentrations, however, the residual activity of the corresponding enzymes is sufficient to break them down. Finally, there is a thiamine-dependent form of maple syrup disease. Thiamine is vitamin B1. It acts as a coenzyme of some enzymes and also influences their activity. Some forms of maple syrup disease only occur when there is a vitamin B1 deficiency or even a normal vitamin B1 concentration. Long-term thiamine administration prevents the disease here.

Diagnose

Maple syrup disease is diagnosed during newborn screening. The concentration of valine, leucine and isoleucine in blood plasma and urine is determined by mass spectroscopy. However, an indicator of maple syrup disease is the presence of alloisoleucine. The branched-chain amino acids also contain the alpha-keto acids. Blood glucose tests reveal hypoglycemia. In addition, significant ketoacidosis can be detected in acute cases. The corresponding enzyme defects can already be detected before birth.

complications

The complications of maple syrup disease arise primarily when treatment is not initiated early. With a successful diagnosis and prompt treatment, there are usually no further complications or symptoms. Patients with maple syrup disease exhibit strict food refusal. This leads to underweight and a weakened immune system. A strong apathy also occurs, which can lead to social complaints and social exclusion. This can also lead to depressiondevelop. In addition to the refusal to eat, the affected person often does not drink enough fluids. This leads to dehydration. The children are affected by convulsions and usually cry longer and louder than normal children. The parents in particular are heavily psychologically burdened by the maple syrup disease. Treatment of the disease is possible without complications with the help of drugs. As a rule, however, the patient is dependent on a low-protein diet, which he will follow throughout his life. With early treatment and control by the doctor, there are no complications in the development of the child.

treatment and therapy

Therapy can be divided into emergency and long-term therapy. Acute metabolic imbalances are treated as part of emergency therapy. The supply of proteins is stopped immediately with the simultaneous administration of complex carbohydrates or glucose to lower the concentration of branched-chain amino acids and prevent the formation of keto acids. Toxic degradation products of amino acid degradation can be removed by blood washing (dialysis) .

Long-term treatment consists of a strict low-protein diet. In order to be adequately supplied with nitrogen, this diet must be supplemented with an amino acid mixture without leucine, valine and isoleucine in the form of powder. It is also important to provide the body with an adequate supply of electrolytes, vitamins and trace elements . If a thiamine-dependent maple syrup disease was identified at the time of diagnosis, between 10 and 800 milligrams of thiamine per day must be supplied. Then no symptoms appear even with a protein-rich diet.

prevention

Since maple syrup disease is a genetic condition, there is no recommendation for its prevention. However, prenatal testing for enzyme defects can be performed. Human genetic counseling is recommended if there is a desire to have children, especially if there is a family history.